ClinVar Miner

Submissions for variant NM_000487.6(ARSA):c.1397C>T (p.Ala466Val)

dbSNP: rs763065602
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000372841 SCV000334679 other not provided 2015-08-25 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001859568 SCV002270539 uncertain significance Metachromatic leukodystrophy 2022-02-13 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 466 of the ARSA protein (p.Ala466Val). This variant is present in population databases (rs763065602, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ARSA-related conditions. This variant is also known as A464V. ClinVar contains an entry for this variant (Variation ID: 282932). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ARSA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV005238825 SCV005883736 uncertain significance not specified 2024-12-03 criteria provided, single submitter clinical testing Variant summary: ARSA c.1397C>T (p.Ala466Val) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249664 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1397C>T has been reported in the literature in trans with a pathogenic variant in related individuals who presented ARSA and GS values within the range of Metachromatic Leukodystrophy patients but were apparently healthy, while it did not segregate in a member of the family who presented with late infantile MLD (Berger_1999). This report does not provide unequivocal conclusions about association of the variant with Metachromatic Leukodystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 9888390). ClinVar contains an entry for this variant (Variation ID: 282932). Based on the evidence outlined above, the variant was classified as uncertain significance.
Gelb Laboratory, University of Washington RCV001859568 SCV005046617 not provided Metachromatic leukodystrophy no assertion provided in vitro

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